Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
Cell Host Microbe. 2018 Feb 14;23(2):191-202.e4. doi: 10.1016/j.chom.2017.12.017. Epub 2018 Jan 18.
Genome-wide association studies have linked polymorphisms in the autophagy gene ATG16L1 with susceptibility to inflammatory bowel disease (IBD). However, the cell-type-specific effects of autophagy on the regulation of chronic intestinal inflammation have not been investigated. Here, we assessed the effect of myeloid-specific or intestinal epithelial cell (IEC)-specific deletion of Atg16l1 on chronic colitis triggered by the intestinal opportunistic pathogen Helicobacter hepaticus in mice. Although Atg16l1 deficiency in myeloid cells had little effect on disease, mice selectively lacking Atg16l1 in IECs (Atg16l1) developed severely exacerbated pathology, accompanied by elevated pro-inflammatory cytokine secretion and increased IEC apoptosis. Using ex vivo IEC organoids, we demonstrate that autophagy intrinsically controls TNF-induced apoptosis and in vivo blockade of TNF attenuated the exacerbated pathology in Atg16l1 mice. These findings suggest that the IBD susceptibility gene ATG16L1 and the process of autophagy within the epithelium control inflammation-induced apoptosis and barrier integrity to limit chronic intestinal inflammation.
全基因组关联研究已经将自噬基因 ATG16L1 的多态性与炎症性肠病 (IBD) 的易感性联系起来。然而，自噬对慢性肠道炎症的调节的细胞类型特异性影响尚未被研究。在这里，我们评估了髓样细胞特异性或肠上皮细胞 (IEC) 特异性缺失 Atg16l1 对肠道机会性病原体嗜肝螺杆菌诱导的慢性结肠炎的影响。尽管髓样细胞中 Atg16l1 的缺失对疾病几乎没有影响，但选择性地在 IEC 中缺失 Atg16l1 的小鼠 (Atg16l1) 发展为严重加重的病理学，伴随着促炎细胞因子分泌增加和 IEC 凋亡增加。使用离体 IEC 类器官，我们证明自噬内在地控制 TNF 诱导的细胞凋亡，体内阻断 TNF 减轻了 Atg16l1 小鼠的加重病理学。这些发现表明，IBD 易感基因 ATG16L1 和上皮细胞内的自噬过程控制炎症诱导的细胞凋亡和屏障完整性，以限制慢性肠道炎症。
